FDA halted esterase inhibitor/hyaluronidase cocktail, but new formulation may be tried.

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Note that this randomized cross-over study found that two dose-ranges of C1-inhibitor + hyaluronidase were effective in reducing the rate of attacks in hereditary angioedema.

Be aware that the study was halted early due to findings of high hyaluronidase antibodies in other studies of the agent.

HOUSTON -- A subcutaneous formulation of human C1 esterase inhibitor (C1INH) given in conjunction with recombinant human hyaluronidase decreased the number of monthly attacks among patients with hereditary angioedema, although the study was stopped early because of FDA concerns about the hyaluronidase, a researcher said here.

And among those given 2,000 units of C1INH plus 48,000 units of hyaluronidase, there was a decrease of 3.24 attacks per month during 8 weeks of treatment, he said.

Hereditary angioedema is a rare disorder characterized by low levels (type I) or nonfunctional (type II) C1INH, and patients experience periodic attacks of swelling of various tissues including the face, abdomen, and extremities. Attacks involving the upper airways can be lethal.

Plasma-derived C1INH is approved for prophylaxis against attacks when given intravenously in doses of 1,000 units every 3 to 4 days.

"But we know from clinical practice that intravenous administration is not always desirable and can lead to some complications, so a subcutaneous formulation would be helpful," he said.

Recombinant human hyaluronidase was developed as a tissue permeability modifier to increase the subcutaneous dispersion of C1INH.

This combination therapy was evaluated in a double-blind crossover trial that initially randomized 47 patients from 24 centers.

They were given either the lower dose and then the higher dose, each for 8 weeks separated by a washout period of 7 to 30 days (group A), or the higher and then lower dose with a 7 to 30-day washout for group B.

However, in August 2013 the study was discontinued because in several other clinical programs there was an unexpected emergence of non-neutralizing anti-hyaluronidase antibodies in 45% of patients. These antibodies did not appear to be associated with adverse clinical effects and were of unknown clinical significance.

The current analysis included the 22 patients who completed both dosing periods of the study.

Participants' median age was 39, the majority were women, and almost all were white. Patients receiving androgen within the week before randomization were excluded, as were those with a history of hypercoagulability or acquired angioedema.

During the course of treatment, patients in group A experienced 1.58 attacks (95% CI 0.88-2.29) per month, while those in group B had 0.97 (95% CI 0.41-1.53) per month.

There was no sequence effect seen on a within-patient treatment comparison.

The most common adverse events were injection site reactions, which occurred in 84% of patients in the lower dose group and in 87% of those in the higher dose group. Injection site extravasation also was observed, more often with the higher dose (20% versus 9%).

However, the volume of fluid given was the same with the two doses, so the reasons for more extravasation in the higher dose group were not entirely clear, according to Riedl.

"Importantly, there were no thrombotic or thromboembolic adverse events," he said. There also were no treatment discontinuations because of adverse events, and no serious adverse events or deaths.

"In summary, this study did not reach full enrollment because of termination, but it did suggest that both doses of the C1 inhibitor coupled with hyaluronidase were generally well tolerated, and there was an observed reduction from baseline in attack frequency," he said.

"The study has been helpful for us to move forward with a new formulation of [the C1 esterase inhibitor] Cinryze," said Jennifer Schranz, MD, of Shire Pharmaceuticals. "We hope to start a phase 3 study soon," she told MedPage Today.

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